This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic 03-MH-101 Biomarkers in mental disorders. Post-traumatic stress disorder (PTSD) is one of the more common and disabling mental illnesses in the US. Recent work has identified distinct gene expression profiles among persons meeting DSM-IV diagnostic criteria for PTSD compared to trauma-exposed persons who did not develop PTSD. Molecular psychiatric studies based upon both candidate gene and whole genome approaches suggest that specific epigenetic profiles are associated with mental illness. Such profiles may plausibly induce the gene expression difference observed in PTSD-affected vs. -unaffected individuals;however, the contribution of epigenetic changes in the etiology of this disorder is currently unknown. We therefore hypothesize that PTSD is accompanied by epigenetic modification of loci whose activity contributes to the disorder. The proposed project will take advantage of a unique opportunity to test this hypothesis using samples obtained from an ongoing, multi-level longitudinal study of Detroit residents, the Detroit Neighborhood Health Study (DNHS). The present study specifically seeks to: (1) Assess whether methylation profiles differ among individuals with current PTSD, those who have once had PTSD but are now PTSD free, and individuals who have been trauma exposed but never developed the disorder, and (2) Assess whether gene expression profiles differ among individuals with current PTSD, those who have once had PTSD but are now PTSD free, and individuals who have been trauma exposed but never developed the disorder. In addition, for individuals presenting with newly developed cases of PTSD, we will test not only the samples collected during wave two of the study, but also the banked, "pre-PTSD" samples from these same individuals obtained during wave one. Thus, the proposed research activity will conduct the first multi-level study of the epigenetic signatures associated with PTSD to date at minimal cost. Identification of such epigenetic variants will facilitate the search for new and/or more effective pharmacological and psychological interventions to prevent or treat the disorder, and will advance our understanding of the etiology of complex mental illnesses such as PTSD. Finally, given the financial difficulties that Detroit residents have experienced over the past several years, the proposed work includes an unprecedented opportunity to uncover how socioeconomic disadvantage may modify the epigenetic signatures observed among individuals affected by PTSD and, most importantly, to employ residents of Detroit-one of the areas worst affected by the current economic downturn-as part of the project. The proposed study will assess methylation and gene expression profiles among PTSD-affected and - unaffected individuals, all of whom are residents of Detroit. The findings from this study will have important public health implications, including identification of candidate epigenetic biomarkers associated with PTSD that may predict the risk for and course of this disorder.